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Interview With Walter Pierpaoli M.D., Ph.D.

Walter Pierpaoli, M.D., is one of the great avant-garde professional researchers and physicians today who are searching for the central cure for aging disorders. He describes himself thus:

"I am not a wizard or a sorcerer but simply a man curious of nature and biology who has spent almost 40 well documented years in the merry companionship of mice, waiting for them to teach me how and why we age and die. My main feature is endurance and a deeply rooted ability to escape from the fashion of science. I have definitely interpreted the biological expression of the genetic programme of aging in the "pineal network," and am now trying to stop and also reverse aging. My solitary path has not yet been followed, but the crowd generates aggressivity and confusion because many motivations in health care are not addressed to disease prevention but, on the contrary, to there maintenance. The "ultimate defiance" has started and the answer can only be through strict scientific documentation. Mice live two to three years, humans sometimes 100 and over. Some may care to wait to see, but in the meantime I protect my pineal gland from aging by using melatonin."

In this interview with Dr. Pierpaoli, we discuss in detail his views on aging and what his research on melatonin, immunity and cyclicity means for all of us.

AAM: Dr. Pierpaoli, perhaps the most obvious first question I should ask you is what is your interpreation of melatonin?

Dr. Pierpaoli: Well Phil, melatonin is ubiquitous, because it is present everywhere in nature. It is highly concentrated in the pineal gland of man, mammalian species and vertebrates. Here it is produced during the night, resulting in a typical "night peak" of melatonin which can be measured in blood. In humans, blood melatonin levels reach their highest night values before sexual maturation, i.e. at puberty and then they constantly decline. The decline of the melatonin night peak signals the progression of aging. We have found and described in many scientific publications and in a bestselling popular book, [Ed.- The Melatonin Miracle, Simon & Schuster, New York, translated into 17 languages] that nocturnal administration of melatonin to aging rodents results into a significant prolongation of their life. Melatonin in fact, when taken chronically in the late evening, protects the pineal gland from aging by simply putting the pineal gland "to sleep!" This means that other molecules are produced in the pineal gland which dramatically postpone and even reverse aging. These other molecules are presently under experimental and clinical testing, but people should be aware that the transplantation of a pineal gland from a young into an old animal delays aging in a very pronounced manner. Melatonin does not itself affect functions such as immunity directly. Melatonin protects from us from aging thanks to its protecting action on pineal function. This interpretation, which is based on experimental work and clinical observations, explains the many beneficial effects of melatonin on all organs and functions.

AAM: So what does aging mean to you?

Dr. Pierpaoli: We have demonstrated that typical metabolic aging is an evolutionary "programme" in the pineal gland that follows a very precise time schedule, which depends on the evolutionary development of mammals. In all mammals, including man, aging follows the strict neuroendocrine programme of growth, puberty and fertility. Aging does not depend on diseases, but diseases can profoundly affect and accelerate aging. Under ideal conditions of life and genetics with no diseases, the programme of aging will take its course until the emergence of a "death clock" in the pineal gland, which is totally separated from aging. Therefore growth, puberty, fertility, aging and death are all expression of the genetically determined neuroendocrine programme of the mammalian brain, endowed in the hypothalamic-pituitary-pineal area of the brain. Evidence is dramatically emerging that aging is amenable to control and reversal, similar to other neuroendocrine mechanisms such as growth and reproduction. There is nothing mysterious in aging, for we can delay and even reverse aging now!

AAM: So why is the pineal gland so important?

Dr. Pierpaoli: The pineal gland or in its Latin and anatomical name the "epiphysis cerebri," is a tiny bean-size brain organ or "gland" which is connected to the brain and to the neuroendocrine/ hormonal and nervous systems, through a complex network of bidirectional links and, in particular, to the anterior hypothalamic nuclei (suprachiasmatic nuclei), the pituitary gland (hypophysis), the eyes (the retina) and via the supracervical nervous ganglia, to the thyroid, the thymus and all other glands such as the adrenals and the gonads.

Thus it is thus clear that, via its direct connections with the brain centers, such as the suprachiasmatic nuclei, it is regulating body temperature and photoperiodic day-night and seasonal variability of hormonal synthesis and secretion. The "pineal master gland" acts as a true "director of the hormonal orchestra" in the course of growth, puberty, fertility and aging. It must be emphasized, however, that the role of the pineal gland in the maintenance of body functions is strictly related to the different evolution of mammalian and other species, in relation to the survival and reproduction need of each species. The need for reproduction is prioritary. Therefore the pineal gland and its "products" are fundamental for reproduction biology. In the course of evolution, the "pineal network" of each species has acquired the capacity to progressively develop and to maintain a "life, aging and death clock." The parallel genetical and developmental, evolutionary course of all species has resulted into a precise "age-clock" for each species. In other words, environmental and reproductive needs have lead to precise "clocks" for each species. Thus the "pineal network" controls the neuroendocrine programme of aging in the brain and scans the time when we grow, when we procreate and when we age. These precisely programmed events are quite distinct. Our experiments with rodents and clinical evidence show that the pineal gland and its "wonder molecules" which have been the target of mockery from "pinealogists" can truly delay and reverse aging. This is achieved by acting on those same mechanisms which make us grow and reproduce!

The pineal gland is the key for understanding aging because it controls from birth to death the circadian and seasonal variability of hormones- which regulate all functions of the body. Death is a precise signal from the pineal gland which is timely programmed and does not depend on aging. This means that we can die at the age of 120 without any disease! We can stop aging and we will be able to interpret also the mechanism of the "death clock."

AAM: A lot is made by antiaging physicians of hormones, particularly to treat the male andropause and female menopause, what’s your view of that?

Dr. Pierpaoli: Andropause is the expression of the progressive decline of reproductive functions in the male. Although the relevance of sexual senescence in males is largely neglected owing to the prejudices and ignorance surrounding the biological relevance of testosterone, many pathologies and symptoms clearly show, in the great majority of men, an insufficient brain regulation of sex hormones (gonadotropins, LH, FSH) with consequent involution of peripheral male sex organs, (e.g. testes) during aging. One of the most frequent pathologies is prostate hypertrophy and consequent urinary problems. Also a sudden or progressive loss of sexual drive, inertia, apathy, depression, muscular weakness is observed. In our experience, those symptoms and deficiencies do not depend on a quantitative deficiency of sex hormones, but rather on a constant and progressive levelling of hormone cyclicity. In fact, all hormones display a day-night rhythmicity which is under pineal-hypothalamic-pituitary regulation. Aging of the brain results into an increasing stiffness, by which I mean a reduced and ineffective feed-back of the mechanisms which regulate hormone secretion. In fact the so-called central feed-back mechanisms do not respond anymore to stimuli, this results in alteration and de-synchronization of hormone secretion. Melatonin, by protecting the central master gland, namely the pineal gland, from aging, maintains and even reconstitutes normal physiological hormone cyclicity in the brain! In other words, our work has shown that it is not the lack of sex hormones which underlines andropause, but rather the pattern of their circadian, day-night secretion.

For women, menopause is the expression of the progressive and sometimes abrupt cessation of monthly menstruations. Perimenopause, those being the years before, during and after menopause, is generally accompanied, in most women, by a very large variety of symptoms, disturbances, and also changes related to decline of hormonal-regulated monthly ovulation. The problem is clearly neuroendocrine and in fact "hormone replacement therapy" (HRT) can produce positive reversal of menopause-related alterations, but HRT also produces side-effects!

We are convinced, on the basis of a clinical trial which has been reported in a scientific journal [Ed.-Experimental Gerontology, February 2001], that melatonin alone or in combination with HRT can dramatically improve the course of menopause, to the extent that it may be able to prolong fertility and even reconstitute cyclic ovulation and menstruations. It is not true that ovaries are worn out! In fact there is a progressive absorption and sclerosis (ovary atresia) which is brain-programmed and does not depend on lack of ova! Melatonin can produce a progressive reconstitution of juvenile secretion of pituitary gonadotropins and thus reverse the course of menopause. The dramatic reconstituting effects of melatonin on the synthesis and secretion of sex hormones had been demonstrated and published by us, however, as a definite confirmation, clear-cut evidence has emerged from the placebo-controlled clinical study in perimenopausal women, which has been published in Experimental Gerontology, February 2001.

AAM: Perhaps the most well known and discussed treatments of aging center on the role of free radicals and antioxidants, in your work what have you made of that?

Dr. Pierpaoli: We do not share the view that aging can be delayed with "anti-oxidants" and "free radical scavengers" and similar fashionable and simplistic interventions! We think that oxidative damage and oxyradical formation, which is a by-product of cell respiration, only minimally and perhaps not at all contributes to aging. No experimental in-vivo or clinical evidence exists that an addition to the daily diet of even very large amount of "anti-oxidants" such as Vitamin E, glutathione and even melatonin itself- which is the most powerful natural antioxidant agent found to date, will influence the course of aging and affect longevity owing to their capacity to neutralize "toxic" hydroxyradicals. We think that the relevance of oxidative damage on the expression and course of aging is minimal. Nature provided many millions of years ago through evolution the process to neutralize oxidative damage! This commercial slogan does not serve the purpose of fighting aging. We do not share the view that the documented anti-aging and life-prolonging effects of melatonin depends entirely on its anti-oxidant activity. Melatonin is produced at night, when stress-produced oxyradicals are minimal. Nocturnal administration of melatonin at a relatively low dosage will simply prevent the pineal gland from synthesizing melatonin, in particular in the course of aging, thus allowing the pineal gland to maintain the capacity to produce other, more basic molecules.

AAM: Many people are aware that much of your research has focused on immunity, how does melatonin play a role in autoimmunity and the immune system?

Dr. Pierpaoli: Melatonin, in particular when combined with zinc, is a very potent and reliable immunopotentiating agent. In our view, melatonin does not act directly but via its synchronizing effects on the entire neuroendocrine system, which totally controls the immune system. Melatonin will also profoundly affect the thymus and cell-mediated, transplantation immunity and thus the resistance to viruses. The effects of melatonin in enhancing immunity are truly dramatic and it seems that they are exerted via utilization of zinc, which, for example, is needed for synthesis and activation of the thymic hormone thymulin. To summarize, melatonin will protect the pineal gland from aging and balance the gland for its optimal juvenile activity. In case of stress, which produces profound immunodepression, melatonin will protect and restore immunity. In adult and elderly people, melatonin will greatly potentiate the protecting effects of vaccinations.

As for autoimmunity, melatonin must be used in autoimmune diseases simply because it will restore a normal immune reaction and the capacity of the immune system to recognize "self" antigens. We have observed complete recovery! The etiology of all autoimmune diseases affecting the skin, the glands, the blood and any other tissue is based on congenital or acquired inability to recognize our own body tissues and thus to mount an autoimmune reaction. Aging itself is largely a hidden, latent and insidious autoimmune process leading to vasculitis (sclerosis of vessels), autoantibodies and cancer. Our work of 40 years has led to the demonstration that immunity is totally under hormonal control. Melatonin will not increase the synthesis of aggressive autoantibodies, on the contrary it will progressively lead to healing of the basic hormonal derangements underlying and initiating the autoimmune process.

AAM: So how do the natural biorhytms of life effect our hormones and our aging?

Dr. Pierpaoli: Rhythmicity, periodicity, cyclicity, daily and seasonal variations of light and temperature have indelibly inprinted the evolution of life on our planet. Nothing escapes the laws of planetary and cosmic variability and life itself in all its living forms has taken its present shape under the control of the sun, the moon, the tides and the rotation of earth around itself and around the sun. In fact, every tiny process or event in our body obeys the natural laws of biorhythmicity! Emergence of a new life in the mother's womb also depends on ovulation, which is a monthly event. Fertility in women is closely linked to lunar cyclicity and cyclical neuroendocrine regulation. Life itself is the maintenance of cyclicity of hormones and cells, while aging and death is exactly the opposite: progressive loss of adaptive cyclicity. All hormones in fact, including the chemical messenger melatonin, follow a strictly individually shaped day-night variability. When we age and we are ready to die because the genetic programme expires, from "cyclically fluctuating" we become "flat". This is the reason why the night melatonin signal in the pineal gland tells us how old, young or deranged we are. An absent (flat) night peak of melatonin in the pineal gland does not necessarily mean that we are going to die immediately, but that we can expect degenerative and autoimmune diseases or cancer. In fact, melatonin protects the pineal gland from aging and thus the body from becoming "hormonally flat" and from developing the typical "diseases of aging" such as cardiovascular and coronary diseases, auto-aggressive diseases and cancer. We can safely prevent this progressive loss of endogenous hormonal rhythmicity by protecting our master gland- the pineal gland, with evening intake of melatonin, especially if it is also combined with some zinc.

AAM: A lot of talk is made by some people about melatonin’s role in cancer, would you care to elaborate on that subject?

Dr. Pierpaoli: Melatonin is no cure for cancer. Its effects on cancer are only visible if associated to a number of immunity-enhancing agents. Melatonin can help improving pineal function in cancer patients, thus allowing a reconstitution of cancer-surveillance, the natural immunological anti-cancer activity. Melatonin administration and prophylaxis, however, will protect from onset of cancer of all kind, including mammary cancer. Cancer is preceded by hormonal changes which deviate the immune system from its cancer-surveillance tasks. Melatonin can restore a deranged immunity and will thus help to correct the neuroendocrine alterations which produce cancer. So by protecting the pineal gland with melatonin will help protect from cancer. However, once cancer is already developed, melatonin will not significantly affect its course, but it will improve the general conditions of the patient and prolong life. The pineal gland is the key for interpreting the causes of aging and cancer, night melatonin will keep the pineal gland young and functioning!

AAM: Another key factor that many people worry about today are their cholesterol levels. Have you found melatonin to play any role for adjusting lipids favorably?

Dr. Pierpaoli: Naturally, lipids/ fats are vital to the body, but an excess of them, especially in a senescent and sick body will rapidly generate cardiovascular diseases. It is hormones which underline lipid metabolism and HDL and LDL cholesterol, total cholesterol, triglycerides and free fatty acids are part of a balanced system which progressively deranges with aging. As such, melatonin can powerfully contribute to the adjustment of lipid metabolism via its balancing effects on the entire neuroendocrine, hormonal system.

If you check your lipids and then take melatonin for one to two months, then check them again, you will realize that the level is going back to normal. This can be even if lifestyle and diet have not changed ! Of course, improvement of life habits, in particular less stress, more sleep and better food will accelerate the lipid-lowering activity of melatonin.

AAM: Are there any further advantages to melatonin for coronary and cardiovascular diseases?

Dr. Pierpaoli: The variety of diseases caused by the degeneration of vessels, which is drastically accelerated by many factors such as genetics, alimentary habits, diabetes, smoke, alcohol, stress, metal or drug poisoning and so on, comprehend a huge variety of symptoms and diseases. The most common of them are coronary, heart diseases and infarction, thrombosis, arterial and venous occlusions, embolism, brain haemorrhage or ictus and heart arithmias. It has been demonstrated that in the commonest of them, namely coronary heart disease and ictus, the patients show an extremely low level of night melatonin [Ed.- Lancet, volume 345, page 1408, 1995]. This low level is an ominous signal for a derangement of pineal function and consequently for the hormonal regulation of the body. It is certainly not melatonin itself which is missing, but melatonin is produced by the pineal gland at night and its absence shows a profound alteration of pineal control of hormones. Although its effects may require a few months, the addition of melatonin to your evening or nocturnal habits may prolong decades to your life, for besides reconstituting a "child’s sleep," while you sleep, melatonin protects the pineal gland and then this "master gland" will be able to synthesize and secrete other more fundamental molecules which regulate all function of cells. In addition, melatonin is also produced by platelets/ thrombocytes, this has powerful anti-aggregating properties and will keep your vessels and capillaries free, elastic and "smooth."

AAM: Another of the things that concerns many people as we get older is depression, clearly no one enjoys the experience, particularly when there doesn’t seem to a good reason for it. Can melatonin help alleviate these symptoms?

Dr. Pierpaoli: Seasonal affective disorders or SAD, with gloomy morning moods and depression are caused by a variety of family, social, neuro-psychological and hormonal alterations and derangements. Depression can be combined with nervousness, anxiety, fear and also be located in the subconscious without being aware of it. As such, many persons adapt to cohabit permanently with depression. Depression is the most dangerous and devastating of all diseases, in so far it deprives us of any joy and motivation of life. Depression blocks and alters mental biochemistry and creates a vicious circle of negative events in the body and in the brain. For centuries induced fear and depression have been utilized by authoritarian and tyrannical religious movements and regimes to enslave people and make them docile and subdued. One very common condition of more or less deep depression is consequent to menopause and andropause and is obviously dependent on the decline of sexual hormones. Melatonin, by reconstituting a juvenile hormonal cyclicity can, better than any drug acting on brain biochemistry, mitigate or cure depression. It restores physiological sleep and cyclicity of sexual hormones, in particular testosterone and estrogens. Short-term effects are visible but the best results in the restoration of a positive and also euphoric morning mood are achieved by a long-term treatment with melatonin, combined of course with additional interventions such as diet, exercise and sexual activity.

AAM: I suppose the best known feature of melatonin has been its reported effect on improving sleep patterns and jet-lag, how do you feel about that?

Dr. Pierpaoli: Well as I think everyone can see, melatonin is a remarkable molecule with many uses. But in regard to sleep, it is its effects on the regular, circadian, e.g. day and night change and cyclic, daily temporary event of life that are most important. Insomnia is a disturbance of sleep duration and quality, leading to severe and often irreparable damage of psychic and somatic functions. I would like people to know that melatonin is not a sleeping pill and has no drug effect on the sleep quality or length. However, thanks to its central action on the re-synchronization of hormonal cyclicity, melatonin reconstitutes a juvenile and physiological sleep pattern.

The reconstituting effect of sleep does not depend on its duration, but on its quality. A normal healthy sleep is characterized by an initial "rapid eyes movement" (REM) phase. If sleep is disturbed such as during "pathological aging," REM sleep disappears. All hormones follow a typical 24-hour cyclicity and variation which is being deranged by many factors such as stress, anxiety, diseases, jet-lag and so on. The melatonin-induced sleep produces a juvenile pattern of sleep with REM which perfectly restores psychic, mental and body forces. In order to cure insomnia, one must recreate a periodicity and quality of sleep which only melatonin can provide. The progressive restoration of hormonal cyclicity produced by protecting the pineal gland with melatonin, acts as a positive cascade which automatically reconstitutes a healthy and profound sleep, with no regard to its duration.

With specific regard to jet-lag, the discomfort, sleep, weakness and psychosomatic and neurovegetative problems provoked by crossing within a short time one or more Oceans and Continents, and resulting in a slow and difficult adaptation to a new local daytime and environment, including the temperature and time of day, can be partially or even totally prevented or overcome by taking melatonin before leaving for a destination or at arrival. The same can be done on the way back home. In order to adapt to the destination time before leaving, one must take for two or three days before departure about 3 mg. of melatonin by calculating the late-evening time at destination of 10 to 12 pm. Then continue to take melatonin after arrival at the detination, when the brain has already adapted to local time before departure. The same must be applied when returning home. One must take melatonin for two-three days before departure by calculating the late-evening time at home. In case a prophylactic adaptation cannot be done, in order to at least mitigate the effects of jet-lag one must take melatonin at the destination place only when going to bed between 10pm and 12 pm and not before! The discomfort of jet-lag becomes very significant when the time difference between home and destination time is more than 6 hours. [Ed.- It has been calculated that the body clock requires 1-day to adapat to each hour of time difference].

AAM: One of the great pleasures I had last year was to be invited to one of your Stromboli conferences. For those whose European geography isn’t good, Stromboli is a unique volcanic island located in the Tyrrhenian Sea off the coast of Sicily. I belive that many people won’t have heard of the conference before, probably because you only invite scientists, physicians and researchers to lecture and network amongst themselves. It is a super event, and in particular I remember one fascinating piece of information imparted by Dr. Changxian Yi from China on the effects of melatonin and vision, do you recall it?

Dr. Pierpaoli: ndeed I do Phil. Firstly let me say that melatonin is produced by the retina. The large clinical trial in China on the protecting and reconstituing effects of evening administration of melatonin were focused on the currently incurable diseases of the eyes that lead to blindness, namely macula degeneration and atrophy, and also in aging-related or diabetes-depending retinopathies. This was done because hundred of millions of persons are affected by fatal macula degeneration. We have documented a single case of retina degeneration close to blindness that was cured with melatonin, the patient having total clinical recovery of the retina and permanent maintenance of residual sight capacity. The almost blind subject even get his driving licence back! The case is described in my "Melatonin Miracle" book and now Dr. Yi has many before and after pictures of reversal of macula degeneration just from the evening administration of oral melatonin!

AAM: The wide range of improvements that you have clinically shown melatonin to be able to perform are truly incredible. Are there any other areas you would like to mention that we haven’t already covered?

Dr. Pierpaoli: Indeed there are some more. For example, to our great amazement and surprise, we have documented several cases of subchronic and chronic hepatitis-C cases which have undergone rapid regression of fatty infiltration and reconstitution of liver tissue, after late evening administration of melatonin, this has been shown by repeated liver biopsy and liver enzymes measurement. The effects are visible within weeks or months after initiation of melatonin intake and depend on the degree of severity of hepatitis as well as individual health conditions and lifestyle such as diet, stress and so on. However, the reconstitution of liver tissue integrity and function was constant and has led to complete healing. We hypothesize a potent local anti-inflammatory effect and a rapid enhancement of anti-viral immunity with melatonin, which has been shown in our experimental work with virus infected mice.

We have also documented the reversal of osteoporosis in women after continued intake of melatonin. This has been documented with regular bone densitometry measurements. This is not astonishing if we consider that melatonin profoundly affects the levels of gonadotropins and reverses the perimenopausal syndrome in women. The positive cascade of events initiated by melatonin are also seen in the reactivation of bone metabolism and bone formation. This is one of the most easily documentable effects of melatonin in arresting and reversing menopause.

Plus there is no doubt that, according to our clinical observations over many years that melatonin can rapidly or slowly ameliorate Parkinson's disease. There is no rule for it in so far the effects of melatonin greatly vary depending upon age, sex, stage of the disease, therapy and so on. However, melatonin is a fundamental therapeutical agent for improving Parkinson’s disease. We have observed patients for years and documented a constant improvement even from advanced Parkinson to its complete healing. The therapy must be continued for many years since sometimes the improvements are suddenly rapid after a long period of administration. A dosage of 3 mg. in the evening appears to be sufficient. In case of strong rigidity, recovery is slower but constant.

Lasltly, let me mention sex power! The idea that melatonin affects sexual vigor is true. However, it would be misleading to think that melatonin is a kind of aphrodisiac drug, a kind of magic "sex-drive-arousing pill!" Melatonin, taken according to a circadian night rhythm certainly protects the pineal gland and thus maintains physiological and juvenile sexuality. Melatonin is not itself a sex hormone but it helps to maintain sexual functions. In spite of the fact that melatonin controls reproductive functions in many species, such as sheep, it does not do so in humans. On the contrary, if taken at a very high dosage in young fertile women, melatonin inhibits secretion of gonadotropins from the pituitary gland and consequently ovulation. If taken at a moderate dosage of a maximum of 3 mg., melatonin protects the reproductive tract both in males and females from sexual decay and aging. By maintaining the normal functions of the sex glands in both men and women, melatonin prolongs a gratifying, juvenile and active sexual life.

AAM: So Dr. Pierpaoli, if I was to ask you for a one line statement about how to use melatonin what would you say?

Dr. Pierpaoli: In conclusion, I recommend a regular nightly intake of melatonin of 3 mg., with additional zinc for all persons more than 40 years old. Melatonin can also be taken by younger persons for periods of weeks or months, especially when under conditions of severe stress, insomnia, jet-lag and a number of pathologies, including autoimmune diseases of all kind.

AAM: Dr. Pierpaoli, thank you very much for your remarkable insight into the amazingly broad properties of melatonin.